To study the role of complement (C) and C receptors (CRs) in controlling B-cell development and the antibody repertoire, humoral immune responses, and spontaneous autoimmunity, we shall generate congenic lines of mice that are deficient for the classical and/or alternate C pathways and for specific combinations of CR ligands. These animals will be used to map genetically the separate and combined roles of Clq, C4, C3, and CR1 and -2 in selective clonal deletion, anergy, and secondary V(D)J rearrangement in developing B lymphocytes, germinal center and serum antibody responses, clearance of dead cells and cellular debris, and the promotion of autoimmunity. We propose that C and CR deficiencies promote self-reactivity by two distinct but mutually supportive pathways: alteration of central tolerance and the B-cell repertoire by the effects of CR1/2 and their ligands and impaired removal of immunogenic cellular debris and immune complexes by Clq and C3. Thus, we propose that the innate immune system controls both the frequency of peripheral, self-reactive B cells and their exposure to antigen.